The present invention relates to glucokinase activators. In particular, the present invention is directed to compounds useful for the treatment of diabetes, especially type 2 diabetes, as well as related diseases and conditions such as obesity and metabolic syndrome.
Glucokinase (GK)(ATP: D-hexose 6-phosphotransferase, EC 2.7.1.1) is one of 4 types of hexokinase (hexokinase IV) in mammals. Hexokinase is an enzyme that acts in the first stage of the glycolytic pathway catalyzing the reaction from glucose to glucose 6-phosphate. Glucokinase is localized mainly in the liver and the beta cells of the pancreas where it controls the rate-determining step of glucose metabolism. Notably, in 3 types of hexokinase (I, II, and III) other than glucokinase, the enzyme activities are saturated at a 1 mM or lower concentration of glucose, whereas the Km of glucokinase for glucose is 8 mM, which value is proximate to the physiological blood sugar level. Therefore, the intracellular glucose metabolism is accelerated through glucokinase in response to the change of blood sugar level from normal (5 mM) to postprandial elevation (10-15 mM).
Results in recombinant mice expressing glucokinase have demonstrated that in fact glucokinase plays an important role in the generalized homeostasis of glucose. Though mice in which the glucokinase gene has been destroyed result in death shortly after birth (Grupe A, et al., “Transgenic knockouts reveal a critical requirement for pancreatic beta cell glucokinase in maintaining glucose homeostasis”, Cell, 83, 1995, P. 69-78.), the blood sugar level is decreased in normal and diabetic mice where glucokinase is generated in excess (Ferre T, et al., “Correction of diabetic alterations by glucokinase”, Proceedings of the National Academy of Sciences of the U.S.A., 93, 1996, P. 7225-7230). With increase of the glucose concentration, the reactions of the pancreatic beta cells and hepatocytes move toward decreasing the blood sugar level.
This means that glucokinase works as a glucose sensor in humans and plays an important role in glucose homeostasis. As such, it is believed that for a large number of type II diabetic patients, it may be possible to regulate blood sugar level utilizing a glucokinase sensor system.
The disclosed glucokinase-activating substances are expected to accelerate insulin secretion in the pancreatic beta cells, and accelerate sugar uptake and inhibit sugar release in liver. Thus, they are considered useful as therapeutic agents in the treatment of type II diabetes.
It has furthermore been elucidated that the occurrence of glucokinase of the pancreatic beta cell type is localized in the brain of rats, particularly in the feeding center (ventromedial hypothalamus; VMH). About 20% of the neurocytes in VMH, called the glucose responsive neuron, are believed to play an important role in control of body weight. Feeding of rats is decreased when glucose is administered into the brain, while inhibition of the glucose metabolism by intracerebral administration of a glucose analog, glucosamine, causes hyperphagia. From electrophysiological experiments, it has been recognized that the glucose responsive neuron is activated in response to the physiological change of glucose concentration (5-20 mM), but its activity is inhibited by inhibiting the glucose metabolism with glucosamine. The same mechanism through glucokinase has been assumed in the sensor system for the glucose concentration in VHM as in the insulin secretion in the pancreatic beta cells. Therefore, in addition to the action in the liver and pancreatic beta cells, a glucokinase-activating substance in VMH is expected to improve not only the blood sugar lever but also obesity which is a problem in a large number of type II diabetic patients.